The high prevalence of ventricular arrhythmias during myocardial ischemia and the association of sudden cardiac death with recurrent ventricular arrhythmias suggests that a better understanding of the electrophysiological basis of cardiac arrhythmias is urgently required. Numerous in vivo studies have established that ventricular epicardium (Epi) is much more susceptible to electrical depression during ischemia than is endocardium (Endo). The mechanism underlying the differential sensitivities and its relation to arrhythmogenesis is currently unresolved. Recently, hovever, the presence of an additional repolarizing current (transient outward current or Ito) has been identified in Epi but is lacking in Endo. The relation of Ito the differential sensitivities of Epi and Endo to ischemia has not been investigated. The proposed studies are designed to examine the differences that exist between Epi and Endo with respect to electrophysiologic characteristies, sensitivities to simulated ischemia and pharmacologic interventions. In particular, the central hypothesis that the presence of a prominent Ito in Epi but not Endo contributes strongly to the selective depression of Epi by ischemia vill be tested in a number of protocols that utilize syncytial cardiac preparations, single dissociated myocytes and successive layers of the ventricular wall. The proposed studies will also explore the relationship between Ito and the slow inward Ca current (isi) in the generation of the action potentia configuration and how this relat on is altered during simulated ischemia. Lastly, the consequences of a differential sensitivity to ischemia in terms of arrhythmogenesis will be investigated, with specific reference to supernormal conduction and reentry. The long range goal of the proposed research is to advance our understanding of the mechanisms by which life-threatening cardiac arrhythmias are intitiated and sustained and thereby provide a more rational basis for their prevention and control.